Matrix Metalloproteinases and Tissue Inhibitor of Metalloproteinases in Inflammation and Fibrosis of Skeletal Muscles.

In skeletal muscles, levels and activity of Matrix MetalloProteinases (MMPs) and Tissue Inhibitors of MetalloProteinases (TIMPs) have been involved in myoblast migration, fusion and various physiological and pathological remodeling situations including neuromuscular diseases. This has opened perspectives for the use of MMPs' overexpression to improve the efficiency of cell therapy in muscular dystrophies and resolve fibrosis. Alternatively, inhibition of individual MMPs in animal models of muscular dystrophies has provided evidence of beneficial, dual or adverse effects on muscle morphology or function. We review here the role played by MMPs/TIMPs in skeletal muscle inflammation and fibrosis, two major hurdles that limit the success of cell and gene therapy. We report and analyze the consequences of genetic or pharmacological modulation of MMP levels on the inflammation of skeletal muscles and their repair in light of experimental findings. We further discuss how the interplay between MMPs/TIMPs levels, cytokines/chemokines, growth factors and permanent low-grade inflammation favor cellular and molecular modifications resulting in fibrosis.

Matrix metalloproteinases in skeletal muscles: friends or foes?

Matrix metalloproteinases (MMPs) are members of an enzyme family that require a zinc ion at their active site. Active at neutral pH, they catalyze normal turnover of extracellular matrix (ECM) and are critical for maintaining tissue allostasis. Subtle coordination between MMP activity and its inhibition by tissue inhibitors of metalloproteinases (TIMPs) insures ECM homeostasis. Loss of control of MMPs expression/activity in numerous pathologies usually associates with host response to injuries, facilitation of disease progression and significant tissue damage. In skeletal muscles, fragmentary knowledge of MMPs/TIMPs regulation and function underscores the need for a better understanding of their role which may lead to therapeutic alternatives. This review presents the current knowledge of MMPs in the biology and pathology of skeletal muscles and puts into perspective therapeutic alternatives that could be challenged in experimental models or that might emerge from in depth investigation of MMPs/TIMPs status in neuromuscular diseases.

MMP-9 overexpression improves myogenic cell migration and engraftment.

Myoblast migration requires matrix metalloproteinase (MMP) activity but the contribution of individual MMPs or tissue inhibitors of matrix metalloproteinase (TIMPs), particularly MMP-9 and TIMP-1, is lacking. Using two clones derived for differential regulation of MMP-2, MMP-9, and TIMP-1, we correlated protein expression with cell migration. MMP/TIMP regulation was determined by zymography, western blots, and quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Cell migration was compared in vitro and after grafting into nude-mdx mouse muscles. C2M9 clones produced high MMP-9 and low MMP-2, and migrated better than C2F clones, which secreted low MMP-9, but overexpressed MMP-2 and TIMP-1. Improvement of C2F invasion by MMP-9 and inhibition of C2M9 migration by MMP-9 inhibitor I confirmed the role of MMP-9 and pointed to potential inhibition by TIMP-1. Higher complementation achieved by C2M9 grafts corroborated the beneficial effect of MMP-9 overexpression. Modulation of MMP-9 expression opens perspectives for improved efficacy of cell therapy for muscular dystrophies.